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Examining the neural targets of the AMPA receptor potentiator LY404187 in the rat brain using pharmacological magnetic resonance imaging

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Abstract

Rationale

Drugs that enhance α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor-mediated glutamatergic transmission, such as the AMPA receptor potentiator LY404187, may form treatment strategies for disorders of cognition, learning and memory.

Objectives

Pharmacological magnetic resonance imaging (phMRI) uses blood oxygenation level dependent (BOLD) contrast as a marker of neuronal activity and allows dynamic non-invasive in vivo imaging of the effects of CNS-active compounds. This study used phMRI to examine the effects of LY404187 in the rat brain.

Method

Groups of Sprague Dawley rats (n=7) were anaesthetised and placed in a 4.7 Tesla superconducting magnet before receiving an acute dose of LY404187 (0.5 mg/kg s.c.), either alone or after pretreatment with the selective AMPA/kainate antagonist LY293558 (15 mg/kg s.c.), or LY293558 alone (15 mg/kg s.c.). Brain images were acquired for each subject every minute for 180 min. These volumes were extensively pre-processed before being analysed for changes in BOLD contrast.

Results

LY404187 produced significant increases in BOLD contrast in brain regions including the hippocampus, lateral and medial habenulae and superior and inferior colliculi. These changes were blocked by LY293558. When administered alone, LY293558 caused widespread decreases in BOLD contrast.

Conclusions

The known actions of LY404187 suggest the observed BOLD signal increases reflect increases in excitatory neurotransmission. The decreases in signal following LY293558 alone are harder to interpret and are discussed in terms of the negative BOLD response. This study provides the first evidence that the effects of AMPA receptor-mediating compounds can be observed using phMRI.

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Acknowledgements

This research was funded by Eli Lilly and Co. Ltd. The MRI spectrometer was provided by the University of London Intercollegiate Research Service scheme and is located at Queen Mary College London managed by Dr. Alasdair Preston.

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Authors and Affiliations

  1. Neuroimaging Research Group, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK

    Nicholas Jones & Steve C. R. Williams

  2. Eli Lilly and Co. Ltd., Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK

    Michael J. O’Neill & Mark Tricklebank

  3. Neurology Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, Essex, CM19 5AW, UK

    Vincenzo Libri

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  1. Nicholas Jones
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  2. Michael J. O’Neill
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  3. Mark Tricklebank
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Correspondence to Nicholas Jones.

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Jones, N., O’Neill, M.J., Tricklebank, M. et al. Examining the neural targets of the AMPA receptor potentiator LY404187 in the rat brain using pharmacological magnetic resonance imaging. Psychopharmacology 180, 743–751 (2005). https://doi.org/10.1007/s00213-005-2254-y

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